Download National Institute of Allergy and Infectious Diseases

Impact of the Xenopus system on the mission of the NIAID
Jaques Robert, PhD – University of Rochester Medical School
It is now well established that both the innate and adaptive immune systems undergo
rapid evolution and diversification; consequently, non-mammalian vertebrate animal
models that are experimentally tractable alternatives to murine systems are essential, as
they will allow us better distinguish important conserved structures and functions from
species-specific specializations. In this regard, Xenopus offers one of the best
comparative models with which to study the immune system.
Indeed, the advantages of the Xenopus model systems have been leveraged to
advance our understanding of many facets of immunity. These include: humoral and
cell-mediated immunity in the context of MHC restricted and unrestricted recognition;
ontogeny; phylogeny; and defense against tumors, viruses, fungi and bacteria (reviewed
in Pasquier et al., 1989; Robert and Ohta, 2009). Xenopus is as valuable as zebrafish for
studying the ontogeny of the immune system. Moreover, unlike zebrafish, Xenopus has
the best characterized immune system outside of mammals and chicken. Furthermore,
the Xenopus model offers a collection of invaluable research tools including MHCdefined clones, inbred strains, cell lines, and monoclonal antibodies. Finally, the
annotated full genome sequence of X. tropicalis and its remarkable conservation of gene
organization with mammals, as well as ongoing genome mapping and mutagenesis
studies in X. tropicalis provide a new dimension to the study of immunity The salient
features of this amphibian model are summarized below.
Model to study Immunogenetics: The X. tropicalis genome has provided
compelling evidence for the similarity of gene repertoire in both the adaptive and innate
immune systems (Zarrin et al., 2004; Guselnikov et al., 2008). More importantly, it has
unveiled the amazing degree of conservation of gene clustering or synteny with
mammals, which is far better preserved with Xenopus than with any fish species whose
genomes have undergone extensive diversification during evolution. Gene synteny is
helpful for identifying diverged genes such as immune genes. For example, in Xenopus
as in mammals CD8 beta retains proximity to CD8 alpha, and CD4 neighbors Lag3 and
B protein. Ongoing whole genome mutagenesis will allow one to search for genes
critically involved in immune functions.
Xenopus is the only genus where polyploid as well as diploid species exist naturally,
and can be artificially produced with various degrees of polyploidy (2N to 8N), enabling
an experimental approach to studying the consequences of whole genome duplication
(i.e., study the fate of duplicated genes), a subject of major interest nowadays for
understanding the origin of the vertebrate genome, as well as the effects of gene dose
on host resistance or defense against pathogens. Xenopus species can also be cloned
using gynogenetic development of diploid eggs coming from interspecies hybrids. These
clones can easily be maintained and propagated in the laboratory, and constitute a
unique in vivo way to study genome regulation. Clones with identical MHC combinations
but differences at minor histocompatibilty (H) gene loci provide an excellent biological
system to study immune responses in vivo. X. laevis is the only species where aneuploid
animals can be generated for studying the segregation of immune functions linked to a
specific chromosome. In situ hybridization techniques are now available both for
chromosome and for whole mounts embryos.
Model to study the development of the immune system: Xenopus provides an
excellent system to study early ontogeny of the immune system. Xenopus has all the
lineages of hematopoietic cells that mammals have. However, early developmental
stages of Xenopus are free of maternal influence, and are easily accessible and
amenable to experimentation. This provides an ideal animals model to study early
commitments and fates of myeloid and lymphoid lineages (Suzuki et al., 2004; Marr et
al., 2007).
Metamorphosis in Xenopus is a truly unique developmental period, in which the
larval thymus loses most of its lymphocytes, and a new differentiation occurs from a
second wave of stem cell immigration resulting in completely distinct adult immune
system. Notably, autoimmunity against the many new adult type proteins needs to be
prevented by a new balance of self-tolerance through T cell education (Flajnik et al.,
2001). This system has the additional advantage of the accessibility of the thymus early
in development. Indeed, thymectomy can be efficiently performed in Xenopus at early
developmental stages before the migration of stem cells and generate T cell-deficient
animals. Therefore, Xenopus has been and still is frequently used to study T cell
ontogeny, and with the new genomic and genetic technologies it offers new ways to
analyze genes and function in a complementary manner.
Model to study immune tolerance. Xenopus serves as an exciting comparative
model to explore self-tolerance because of the ease with which allotolerance to minor HAgs on adult skin grafts can be induced just prior or during metamorphosis that is the
transitional animal undergoes a temporary period of altered immunoregulation (Flajnik et
al., 2001). During this period, one can experimentally induce long-lasting specific nondeletional (“split”) anergic-like tolerance to minor H-Ags that persists after
metamorphosis. MHC genes are also differentially regulated in larvae and adults. The
change in MHC gene regulation during metamorphosis, the new histogenesis in the
thymus, and the ease with which one can experimentally manipulate larvae (e.g.,
thymectomy, blocking or accelerating metamorphosis) allows one to address questions
about MHC restriction, autoimmunity, and the development of self-tolerance that can not
be easily studied in other animal models.
Model to study tumor immunity: Xenopus is the only amphibian genus where
series of true lymphoid tumors have been discovered and cell lines have been obtained,
thereby opening up new avenues for tumor biology and the isolation and
characterization of membrane proteins. In particular, distinct immune systems of larvae
and adults, and the ease of manipulating their maturation during metamorphosis
provides a unique to investigate in vivo the possible influence of the immune system on
the selection of more aggressive tumor. Xenopus has also significantly helped to
demonstrate the importance of certain heat shock proteins such as hsp70 in anti-tumor
immune responses. It provides a natural in vivo model to dissect the contribution of
innate (pro-inflammatory) and adaptive (MHC class I restricted T cell) arm of the immune
system in hsp-mediated anti-tumor responses (Goyos et al., 2007). As such Xenopus is
an important comparative tumor immunity model that can contribute to designing more
efficient immunotherapeutic approaches to control cancer.
Model to study vascular and lymphatic transdifferentiation and regeneration.
The Xenopus tadpole has recently emerged as a very powerful system for tissue and
vasculature regeneration research (Slak et al., 2008). Within 7-10 days following
amputation, a completely new functional tail, with all its tissue types (including muscles,
spinal cord, etc) regenerates in this system. Formation, maintenance and regeneration
of lymphatics and blood vessel have become a major area of investigation in their own
right, as well as owing to on immune function and immune responses (Ny et al., 2005;
2008; Fukazawa et al., 2009)
Model to study immune responses to important emerging infectious diseases:
Xenopus provides a powerful laboratory model to study immunity to important emerging
infectious diseases caused by a chitrid fungus and by ranaviruses (Iridoviridae). The
recognized threat of these emerging wildlife diseases on global biodiversity, which
ultimately impacts on human health, makes it urgent to better understand host-pathogen
interactions in vertebrates other than mammals. Because of the extent to which
knowledge has already been acquired, as well as the availability of tools including
microarrays and genomic information, Xenopus is an ideal model for such studies. For
example, comparison between susceptible tadpoles and resistant adults to ranaviral
infection, and between susceptible X. tropicalis and resistant X. laevis to chytrid fungal
infection, provide ways to elucidate virulence and immune escape mechanisms that are
of high fundamental relevance (Morales and Robert, 2007; Rosenblum et al., 2009). The
unique antimicrobial peptides in skin secretions produced by Xenopus are very potent
against HIV and many human gram negative and positive bacteria, and therefore are of
high biomedical interest. Available genomic information will provide further insight about
the regulation and evolution of the genes encoding these proteins (Zasloff, 2002).
Generation and maintenance of animal and tools: Invaluable research tools for X.
laevis including monoclonal antibodies (mAbs), antisera, cell lines, genomic, cDNA, and
EST libraries have been accumulated since 1976 and are maintained for the scientific
community in a research resource funded by NIAID. This resource also maintains MHCdefined and clones that permit classic adoptive transfer and transplantation
manipulations (e.g., skin grafting) as in mice. Unlike mice, however, they also permit
transfer of tissues and cells between larva and adult. Material and animals have been
provided for more than 40 laboratories worldwide. Recently, inbred strains of X. tropicalis
have also been established.
Several transgenesis techniques are now operational for both X. laevis and X.
tropicalis, and transgenic lines with fluorescence reporter genes specifically expressed
by myeloid cells are available (ref. Other transgenic lines are under development. A
relatively large panel of mAbs including anti-MHC, and anti-B, T, NK and general
leukocyte markers are available for X. laevis and more are currently being generated
using novel technologies such as phage displays of single chain Abs. Generation of
Xenopus -specific Abs is among the priorities identified by the Xenopus community. The
combined use of transgenic lines with cell types expressing fluorescence reporter genes
and flow cytometry cell sorting using available mAbs to isolate specific cell subsets with
the possibility of transferring these cells to embryos or adult recipients will make
Xenopus an even more valuable model in the next decade.
In summary, Xenopus provides a unique, versatile, non-mammalian model with
which to investigate important contemporary issues of immunity such as, ontogeny of
immunity, self-tolerance, autoimmunity, tumor immunity, and adaptation of host immune
defenses to emerging pathogens. The recent genomic and genetic technologies
developed in Xenopus has the potential to make Xenopus a one of the most powerful
and innovative comparative models for immunological and biomedical research.
Selected references:
1. Du Pasquier L, Schwager J, Flajnik MF. 1989. The immune system of Xenopus. Annu
Rev Immunol 7:251-275.
2. Flajnik MF, Kasahara M. 2001. Comparative genomics of the MHC: glimpses into the
evolution of the adaptive immune system. Immunity 15:351-362.
3. Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady
G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA,
O'Neill LA. 2001. Mal (MyD88-adapter-like) is required for Toll-like receptor-4
signal transduction. Nature 413:78-83.
4. Fukazawa T, Naora Y, Kunieda T, Kubo T. 2009.Suppression of the immune
response potentiates tadpole tail regeneration during the refractory period.
Development. 136:2323-2327.
5. Goyos A, Guselnikov S, Chida AS, Sniderhan LF, Maggirwar SB, Nedelkovska H,
Robert J. 2007. Involvement of nonclassical MHC class Ib molecules in heat shock
protein-mediated anti-tumor responses. Eur J Immunol. 37:1494-501.
6. Guselnikov SV, Ramanayake T, Erilova AY, Mechetina LV, Najakshin AM, Robert J,
Taranin AV. 2008. The Xenopus FcR family demonstrates continually high
diversification of paired receptors in vertebrate evolution. BMC Evol Biol. 8:148.
7. Marr S, Morales H, Bottaro A, Cooper M, Flajnik M, Robert J. 2007. Localization and
differential expression of activation-induced cytidine deaminase in the amphibian
Xenopus upon antigen stimulation and during early development. J Immunol.
179:6783-6789.
8. Morales, H.D. and Robert, J. (2007). In vivo characterization of primary and
secondary anti-ranavirus CD8 T cell responses in Xenopus laevis. J. Virol.
81:2240-2248.
9. Ny A, Koch M, Schneider M, Neven E, Tong RT, Maity S, Fischer C, Plaisance S,
Lambrechts D, Héligon C, Terclavers S, Ciesiolka M, Kälin R, Man WY, Senn I,
Wyns S, Lupu F, Brändli A, Vleminckx K, Collen D, Dewerchin M, Conway EM,
Moons L, Jain RK, Carmeliet P. 2005. A genetic Xenopus laevis tadpole model to
study lymphangiogenesis. Nat Med. 11:998-1004.
10. Ny A, Koch M, Vandevelde W, Schneider M, Fischer C, Diez-Juan A, Neven E,
Geudens I, Maity S, Moons L, Plaisance S, Lambrechts D, Carmeliet P, Dewerchin
M. (2008). Role of VEGF-D and VEGFR-3 in developmental lymphangiogenesis, a
chemicogenetic study in Xenopus tadpoles. Blood. 112:1740-1749.
11. Ohta Y, Goetz W, Hossain MZ, Nonaka M, Flajnik MF. 2006. Ancestral organization
of the MHC revealed in the amphibian Xenopus. J Immunol 176:3674-3685.
12. Ohta Y, Flajnik M. 2006. IgD, like IgM, is a primordial immunoglobulin class
perpetuated in most jawed vertebrates. Proc Natl Acad Sci U S A 103:1072310728.
13. Robert J, Cohen N. 1998. Evolution of immune surveillance and tumor immunity:
studies in Xenopus. Immunol Rev 166: 231-243.
14. Robert, J. and Ohta, Y. 2009. Comparative and developmental study of the immune
system in Xenopus. Dev. Dyn. 238:1249–1270.
15. Rosenblum EB, Poorten T, Settles M, Murdoch G, Robert J, Maddox N, and Eisen
MB. (2009). Genome wide transcriptional response of Silurana (Xenopus) tropicalis
to infection with the deadly Chytrid fungus.
16. Slack, J.M., G. Lin, and Y. Chen, The Xenopus tadpole: a new model for
regeneration research. Cell Mol Life Sci, 2008. 65(1): p. 54-63.
17. Silva AB, Aw D, Palmer DB. 2006. Evolutionary conservation of neuropeptide
expression in the thymus of different species. Immunology. 118(1):131-40.
18. Smith SJ, Kotecha S, Towers N, Latinkic BV, Mohun TJ. 2002. XPOX2-peroxidase
expression and the XLURP-1 promoter reveal the site of embryonic myeloid cell
development in Xenopus. Mech Dev 117:173-186
19. Suzuki M, Takamura Y, Maéno M, Tochinai S, Iyaguchi D, Tanaka I, Nishihira J,
Ishibashi T. 2004 Xenopus laevis macrophage migration inhibitory factor is
essential for axis formation and neural development. J Biol Chem. 279:2140621414.
20. VanCompernolle SE, Taylor RJ, Oswald-Richter K, Jiang J, Youree BE, Bowie JH,
Tyler MJ, Conlon JM, Wade D, Aiken C, Dermody TS, KewalRamani VN, RollinsSmith LA, Unutmaz D. 2005. Antimicrobial peptides from amphibian skin potently
inhibit human immunodeficiency virus infection and transfer of virus from dendritic
cells to T cells. J Virol. 79:11598-11606.
21. Zarrin AA, Alt FW, Chaudhuri J, Stokes N, Kaushal D, Du Pasquier L, Tian M. 2004.
An evolutionarily conserved target motif for immunoglobulin class-switch
recombination. Nat Immunol.5:1275-1281.
22. Zasloff, M. 2002. Antimicrobial peptides of multicellular organisms, Nature 415:389395.
Xenopus grants funded by the Institute:
According to NIH RePORTER Search Tool, in the fiscal year of 2011, the
National Institute of Allergy and Infectious Diseases (NIAID) funded fourteen
grants for projects involving Xenopus. These grants total to $7,762,913
2011 Xenopus White Paper - Community Needs:
Executive Summary
Xenopus: An essential vertebrate model system for biomedical research:
Model animals are crucial to advancing biomedical research. Basic studies in
vertebrate animals rapidly accelerate our understanding of human health and disease.
Among the commonly used model animals, the frog, Xenopus, has great impact
because of its close evolutionary relationship with mammals. Moreover, the remarkable
experimental repertoire of the Xenopus system has made it a cornerstone of
neurobiology, physiology, molecular biology, cell biology, and developmental biology.
Current NIH investment in research using Xenopus:
Consistent with its broad utility, the NIH has made a large and continuing investment
in Xenopus research. Indeed, a search of the NIH rePORT database for R01 or
equivalent grants using the search term “Xenopus” returned 678 grants for a total of
over $217,000,000 for FY09-10. The NIH has also recently demonstrated its
commitment to Xenopus community resources by approving $2.5 million to establish the
National Xenopus Resource in Woods Hole, MA and a similar amount to maintain and
expand Xenbase, the Xenopus Community’s online database.
Xenopus as a model system for human disease gene function
Given the tremendous power of the Xenopus system, the pace of new biological
discovery by the Xenopus Community is vigorous. Using Xenopus, we have significantly
improved our understanding of human disease genes and their mechanisms of action,
justifying the NIH’s investment. For example:
Xenopus embryos are used for in vivo analysis of gene expression and function:
Congenital Heart Disease – PNAS 2011. 108, 2915-2920
CHARGE Syndrome – Nature 2010. 463, 958-962.
Bardet-Biedl and Meckel-Gruber Syndromes – Science 2010. 329, 1337-1340.
Hereditary hypotrichosis simplex – Nature 2010. 464, 1043-1047.
Hutchison-Gilford Progeria – Dev. Cell 2010. 19, 413-25.
Cutis laxa – Nat Genet. 2009. 41, 1016-21.
Colorectal cancer – Genome Res. 2009. 19, 987-93.
Nephronophthisis – Hum Mol Genet. 2008. 17, 3655-62; Nat Genet. 2005. 37, 537-43.
Xenopus egg extracts are used for in vitro biochemical studies:
Fanconi Anemia – Mol. Cell. 2009. 35, 704-15; Science. 2009, 326, 1698-701.
C-myc oncogene – Nature. 2007. 448, 445-51.
BRCA1 – Cell. 2006. 127, 539-552
Xenopus oocytes are used to study gene expression and channel activity:
Rapid-onset dystonia-parkinsonsim – Nature 2010. 467, 99-102.
Trypanosome transmission – Nature 2009. 459, 213-217.
Epilepsy, ataxia, sensorineural deafness – N Engl J Med. 2009. 360, 1960-70.
Catastrophic cardiac arrhythmia (Long-QT syndrome) – PNAS 2009. 106,13082-7.
Megalencephalic leukoencephalopathy – Hum Mol Genet. 2008. 17, 3728-39.
Xenopus as a model system for understanding basic biological processes:
Xenopus also plays a crucial role in elucidating the basic cellular and biochemical
mechanisms underlying the entire spectrum of human pathologies. Just a small fraction
of the many recent discoveries are highlighted here:
Xenopus contributes to our understanding of vertebrate genome organization.
(Science. 2010. 328, 633-636).
Xenopus egg extracts reveal fundamental aspects of cell division.
(Cell. 2010. 140, 349-359; Nature. 2008. 453, 1132-6; Science. 2008. 319, 469-72).
Xenopus reveals new aspects of eukaryotic nuclear structure and function.
(Cell. 2010. 143, 288-98; Science. 2010. 318, 640-643).
Xenopus embryos are used for studies of Wnt and TGF- signal transduction.
(Science. 2010. 327, 459-463; Cell. 2009. 136,123-35).
Xenopus embryos are used for studying mucociliary epithelia.
(Nat Cell. Biol. 2009 11 1225-32; Nature. 2007. 447, 97-101).
Xenopus embryos are used for studying development of the vasculature.
(Cell. 2008.135, 1053-64).
Xenopus egg extracts provide key insights into DNA damage responses.
(Mol Cell. 2009. 35,704-15; Cell. 2008.134, 969-80).
Xenopus embryos link telomerase to Wnt signaling.
(Nature. 2009. 460, 66-72).
Xenopus are used for small molecule screens to develop therapeutics.
(Nat Chem Biol. 2010. 6, 829-836; Blood. 2009. 114, 1110-22; Nat Chem Biol. 2008. 4, 119-25).
Despite its demonstrated utility and despite the recent investments by the NIH,
Xenopus still lacks many resources that are considered entirely essential for other model
systems. It is the consensus of the Xenopus community that their biomedical research
could be greatly accelerated by the development of key resources of use to the entire
Xenopus research community.
At the 2010 International Xenopus Conference, developmental, cell, and molecular
biologists gathered to discuss the resources needed and the priority that should be
assigned to each. There was broad community-wide consensus that eleven resources
are currently needed, and these were prioritized into two categories: Immediate Needs
and Essential Resources:
The Immediate Needs of the Xenopus research community:
1. Generation of the Xenopus ORFeome:
-Will enable genome-wide in vivo analyses of gene function.
-Will enable genome-wide in vivo analyses of protein localization.
-Will enable, when combined with transgenesis, the first large-scale biochemical
determination of protein-protein interactions in specific tissues and at specific
embryonic stages.
-Will facilitate more-rapid functional characterization of specific proteins.
2. Improvement of the Xenopus genome sequence:
-Will accelerate molecular studies by providing a complete catalogue of Xenopus
genes.
-Will enable completion of the Xenopus ORFeomes.
-Will enable genomic analyses & systems biology approaches for novel gene
discovery.
-Will facilitate proteomics approaches and peptide analysis.
Essential Resources for Xenopus research community:
In addition to these most-pressing needs, the community has identified nine other
Essential Resources that should be developed as soon as possible, so that Xenopus
biologists can more effectively fulfill the missions of the NIH. The Xenopus community
considers all of these additional resources to be essential, but understands that priorities
must be set, and therefore ranks these as indicated below:
Improvement of long-range contiguity in the Xenopus laevis
genome
4. Improvement of Xenopus antibody resources
5. Loss of function: Zinc Finger Nucleases/TILLING
6. Loss of function: Small inhibitory hairpin RNAs
7. Novel loss of function/knockdown/knockout technologies
8. Intergenic annotation of the Xenopus genome
9. Improvements of the X. tropicalis genome – long range contiguity
10. Additions and improvements to Xenbase: the Xenopus Model
Organism Database
11. Frogbook: A comprehensive resource for methods in Xenopus
biology
3.
Community Recommendations for Attaining Resources:
The Xenopus Community feels that in order to attain these much needed
resources it will be imperative to renew the PAR-09-240/1: “Genetic and Genomic
Analyses of Xenopus”. This mechanism can help to direct funding to the establishment
of resources that will accelerate research by the entire community. Development of
research resources is essential to the NIH mission, but because such work is not
hypothesis-driven, these proposals fare poorly in standard CSR study sections.
Moreover, the standard study sections typically lack the depth of expertise that is
needed to properly evaluate these proposals. The “Genetics and Genomic Analyses of
Xenopus” PAR allows for a focused and expert review of resource development
proposals, and its renewal will help to ensure a continuing return on the current NIH
investment in biomedical research using Xenopus.
The Xenopus Community also feels that, given the ease with which massive
amounts of biological samples can be obtained using this organism, a new PAR to
support systems biology using Xenopus is warranted. A new PAR in this area would
allow all biomedical researchers to exploit the emerging genomic resources for Xenopus
to perform systems-level analyses in vivo, in a vertebrate, and in a cost-effective
manner. Such research would generate significant advances into the “New Biology”
described below.
Anticipated Gains for Biomedical Research:
Xenopus as an animal model continues to have a broad impact for biomedical
research. Given its already long history of large-scale screens of gene function and its
broad use in molecular, cell, and developmental biology, the establishment of additional
community-wide resources will greatly facilitate the impact of Xenopus as a premier
vertebrate model for systems-level analyses.
The National Research Council and the National Academy of Sciences have recently
called on the United States “to launch a new multiagency, multiyear, and
multidisciplinary initiative to capitalize on the extraordinary advances recently made in
biology”. This report (http://www.nap.edu/catalog.php?record_id=12764) recommends
the term "New Biology" to describe an approach to research where “physicists, chemists,
computer scientists, engineers, mathematicians, and other scientists are integrated into
the field of biology.” The promise of systems-level analysis in Xenopus, combined with
its already proven strengths, make Xenopus the ideal model organism for pursuing “New
Biology.”
Specifically, genome improvements will provide Xenopus researchers with the ability
to perform genome-wide screens for biological activities that will in turn allow the rapid
assembly and analysis of gene regulatory networks and their relationship to phenotypes.
The ORFeome will greatly facilitate such genome-wide screening by allowing all ORFs
to be rapidly analyzed or large numbers of proteins to be tagged for analysis of proteinprotein interaction or for in vivo visualization. Using extracts and biochemical purification
coupled with mass-spectrometry and genomic sequence, protein interactomes can be
rapidly identified and validated. Xenopus offers a unique resource because it is the only
in vivo vertebrate animal model that couples vast amounts of biological material and a
sequenced genome, thus cell-type specific interactomes can also be identified. Largescale genetic screens will identify important novel genes in developmental pathways,
especially given the relatively simple genome of X. tropicalis compared to zebrafish.
Finally, the flexibility of both Xenopus extracts and embryos make this system ideal for
chemical biology screens.
Identifying gene-regulatory networks, interactomes, and novel genes will be only the
first steps. The well-established power of Xenopus for rapid analysis of gene function
will then allow deeply mechanistic analyses to complement the systems-level
approaches described above. It is the combination of these characteristics that
distinguishes Xenopus from other vertebrate model systems such as mouse and
zebrafish and allows for a systems-level approach to understanding biological
mechanisms. The tremendous impact of the Xenopus model cannot be realized,
however, without the immediate development of community-wide research resources.
This White Paper presents the needed resources, and we look to the NIH for guidance in
how to best achieve these goals.
For complete details of the 2011 Xenopus White Paper,
please visit
http://www.xenbase.org/community/xenopuswhitepaper.do
Appendix
Project
Number
Project Title
Activity Principal
Investigator
Organization
Name
Total Cost
5F31AI08018302
EFFECTS OF A
CHLAMYDIAL ATPCONSUMING ENZYME
ON THE
INFLAMMASOME
F31
AVILA, MARIA
LUISA
UNIVERSITY OF
CALIFORNIA,
MERCED
$32,522
5K22AI07388802
ORIGINS OF
SPECIALIZED
MUCOSAL
LYMPHOCYTE SUBSETS
AND
IMMUNOGLOBULIN
ISOTYPES
K22
CRISCITIELLO,
MICHAEL
FREDERICK
TEXAS
AGRILIFE
RESEARCH
$108,000
5R01AI02787720
ONTOGENY AND
PHYLOGENY OF THE
MHC
R01
FLAJNIK,
MARTIN F.
UNIVERSITY OF
MARYLAND
BALTIMORE
$385,484
Contract
GENOMIC
SEQUENCING CENTERS
FOR INFECTIOUS
DISEASES
AWARD OF PART B - IN
VITRO TESTING
RESOURCES FOR AIDS
THERAPEUTICS
DEVELOPMENT
N01
FRASERLEGGETT,
CLAIRE
UNIVERSITY OF
MARYLAND
BALTIMORE
$96,000
N01
HEIL,
MARINTHA
SOUTHERN
RESEARCH
INSTITUTE
$2,802,585
1ZIAAI00091409
GENERATION AND
CHARACTERIZATION
OF ROTAVIRUS VIRUSLIKE PARTICLE (VLP)
VACCINES
ZIA
HOSHINO,
YASUTAKA
NATIONAL
INSTITUTE OF
ALLERGY AND
INFECTIOUS
DISEASES
$226,171
1ZIAAI00109902
T-CELL RECEPTOR
REPERTOIRES IN
IMMUNE REGULATION
AND RESPONSE
ZIA
MILNER,
JOSHUA
$402,156
5R01AI05769505
SNPS IN HANDLING OF
SMALL POX
ANTIVIRALS AND
OTHER DRUGS
NOTCH REGULATION
OF HEMATOPOETIC
CELL FATES
R01
NIGAM, SANJAY
NATIONAL
INSTITUTE OF
ALLERGY AND
INFECTIOUS
DISEASES
UNIVERSITY OF
CALIFORNIA
SAN DIEGO
R01
PEAR, WARREN
Contract
5R01AI04783310
$329,612
UNIVERSITY OF $371,317
PENNSYLVANIA
5R21AI08471102
A NEW INSIGHT INTO
HIV-1 LATENCY
THROUGH A NOVEL IN
VITRO SYSTEM
R21
ROMERIO,
FABIO
UNIVERSITY OF
MARYLAND
BALTIMORE
$191,836
5R01AI04951208
PURINE PATHWAYS
AND INHIBITOR
DESIGN IN
PLASMODIUM
R01
SCHRAMM,
VERN L.
ALBERT
EINSTEIN COL
OF MED
YESHIVA UNIV
$490,845
UH2
STORCH,
GREGORY A.
WASHINGTON
UNIVERSITY
$250,000
NATIONAL
INSTITUTE OF
ALLERGY AND
INFECTIOUS
DISEASES
WESTERGAARD, ALPHA
GREG
GENESIS, INC.
$959,273
3UH2AI083266- THE HUMAN VIROME
01S2
IN CHILDREN AND ITS
RELATIONSHIP TO
FEBRILE ILLNESS
1ZIAAI00035428
IMMUNOREGULATORY ZIA
DEFECTS IN
INFLAMMATORY
BOWEL DISEASE
Contract
NONHUMAN PRIMATE
BREEDING COLONY
N01
STROBER,
WARREN
Total
$1,117,112
$7,762,913